The emergence of enterococci resistant to Vancomycin has been increasing over the past decade. Given that vancomycin is the last defense against many Gram-positive organisms, including methicillin-resistant staphylococcus aureus (MRSA), there is an urgency for new antibiotics. In recent years, research has focused on glycopeptides that are structurally similar to vancomycin in the search for new antibiotics that may be active against these resistant strains, including Vancomycin-Resistant Enterococci (VRE). A82846 glycopeptide analogs have been shown to be some of the most active glycopeptides against a broad range of multi-drug resistant organisms. (see, e.g., U.S. Pat. Nos. 5,591,714 and 5,840,684; and Cooper, R. D. G., N. J. Snyder, M. J. Zweifel, M. A. Staszak, S. C. Wilkie, T. I. Nicas, D. L. Mullen, T. F. Butler, M. J. Rodriguez, B. E. Huff, and R. C. Thompson, “Reductive Alkylation of Glycopeptide Antibiotics: Synthesis and Antibacterial Activity,” J. Antibiotics, 49 (6) 575-581 (1996)).
The natural A82846 analogs and Vancomycin are from the same general class of glycopeptides and have very similar structures. The major difference involves the presence of a 4-epi-vancosaminyl sugar at the benzylic hydroxyl of the sixth amino acid in the A82846 analogs and the different stereochemistry at the 4-position of the amino sugar in the disaccharide of the A82846 analogs as opposed to vancomycin. In general, these changes result in an increase in antibiotic activity. A82846 analogs have been shown to be more active than vancomycin against enterococci and equally as active against most staphylococcus strains.
Synthetic modifications of glycopeptide antibiotics can be difficult due to their complex structures and their insolubility in reaction solvents. There are many conditions disclosed in the literature for amino acid acylations, a number of which have been successfully used for the acylation of vancomycin. For example, U.S. Pat. Nos. 4,639,433; 4,643,987; and 4,698,327 describe the preparation of N-acyl derivatives of the glycopeptides vancomycin, A51568A, A51568B, M43A and M43D. (See also Nagarajan, R., A. A. Schabel, J. L. Occolowitz, F. T. Counter, and J. L. Ott, “Synthesis and antibacterial activity of N-acyl vancomycins,” J. Antibiotics, 41 (10), 1430-1438 (1988).) However, most of these conditions do not result in acylated products of A82846B. Unlike vancomycin, there are 3 separate sites of acylation in the A82846 analogs: the 2 saccharide amino groups (N1 and N2) and the N-terminal N-methyl leucine nitrogen (N3), which can result in 7 different products, 3 mono-, 3 di-, and 1 tri-substituted products.
U.S. Pat. No. 5,591,714 describes the acylation of A82846A, A82846B, A82846C, and PA-42967-A. However, the conditions described therein do not provide guidance on how to selectively acylate either the N1 and N2 positions or the N3 position. Therefore, there is a need for an improved method for selectively acylating the A82846 glycopeptide analogs.